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Increased sensitivity to 1-β-d-arabinofuranosylcytosine in P388 murine leukemic cells resistant to etoposide

1989; Elsevier BV; Volume: 13; Issue: 1 Linguagem: Inglês

10.1016/0145-2126(89)90029-5

1873-5835

Masamune Higashigawa, Masaru Ido, Toshiki Ohkubo, Hajime Kawasaki, Hitoshi Kamiya, Minoru Sakurai, Kiyosu Taniguchi, Minoru Hamazaki,

Testicular diseases and treatments

A variant P388 murine leukemic cell resistant to 4′-demethylepipodophyllotoxin-9-(4,6-O-ethylidine)-β-d-glucopyranoside (etoposide) (VP-16-213) was cloned. The variant P388/VP-16 cell line was 159-fold resistant to VP-16. We found that this variant P388/VP-16 cell line showed collateral drug sensitivity to 1-β-d-arabinofuranosylcytosine(Ara-C), determined by comparing the 50% inhibitory concentrations in 48-h growth inhibition assay. To clarify the mechanism of this increased sensitivity to Ara-C, we quantified the deoxyribonucleoside triphosphate pools and 1-β-d-arabinofuranosylcytosine triphosphate(Ara-CTP) using high-performance liquid chromatography in the parent and drug-resistant sublines of P388 cells. The analysis of deoxyribonucleoside triphosphate pools revealed that the pyrimidine triphosphate pools were significantly decreased in the P388/VP-16 cell line and the Ara-CTP concentration of two variant cell lines were not significantly different. The Ara-CTP/dCTP ratio was significantly increased in P388/VP-16 cells. These data suggest that the inhibition of the dCTP de-novo pathway and the preservation of the dCTP salvage pathway in P388/VP-16 cells might correlate with the increased sensitivity to Ara-C.